Stroke Mimics in the Acute Setting: Role of Multimodal CT Protocol.

BACKGROUND AND PURPOSE: Ischemic stroke can be mimicked by nonischemic conditions. Due to emphasis on the rapid treatment of acute ischemic stroke, it is crucial to identify these conditions to avoid unnecessary therapies and potential complications. We investigated the performance of the multimodal CT protocol (unenhanced brain CT, CTA, and CTP) to discriminate stroke mimics from acute ischemic stroke. MATERIALS AND METHODS: We retrospectively selected multimodal CT studies performed for clinical suspicion of acute ischemic stroke in our center in a 24-month period, including patients with at least 1 follow-up imaging study (brain CT or MR imaging). Hemorrhagic strokes were excluded. We measured the performance of multimodal CT, comparing the original diagnostic results with the final clinical diagnosis at discharge. RESULTS: Among 401 patients, a stroke mimic condition was diagnosed in 89 (22%), including seizures (34.8%), migraine with aura attack (12.4%), conversion disorder (12.4%), infection (7.9%), brain tumor (7.9%), acute metabolic condition (6.7%), peripheral vertigo (5.6%), syncope (5.6%), transient global amnesia (3.4%), subdural hematoma (1.1%), cervical epidural hematoma (1.1%), and dural AVF (1.1%). Multimodal CT sensitivity, specificity, and accuracy were 24.7%, 99.7%, and 83%. Multimodal CT revealed peri-ictal changes in 13/31 seizures and diagnosed 7/7 brain tumors, 1/1 dural AVF, and 1/1 subdural hematoma. CT perfusion played a pivotal diagnostic role. CONCLUSIONS: Multimodal CT demonstrated low sensitivity but high specificity in the diagnosis of stroke mimics in the acute setting. The high specificity of multimodal CT allows ruling out stroke and thereby avoiding unnecessary revascularization treatment in patients with diagnosis of a stroke mimic.

Intermediate to long-term clinical outcomes and survival analysis of the Salto Mobile Bearing total ankle prothesis.

INTRODUCTION: Osteoarthritis of the ankle is a major burden to affected patients. While tibio-talar arthrodesis has been the gold-standard regarding the treatment of osteoarthritis of the ankle joint for many years, at present total ankle arthroplasty (TAA) provides appealing clinical outcomes and is continually gaining popularity. The aim of this study was to evaluate the intermediate- to long-term clinical outcome including the survival rate of Salto Mobile Bearing TAA (Tonier SA, Saint Ismier, France). MATERIAL AND METHODS: In this retrospective study intermediate- to long-term outcomes measures [Ankle Range of Motion (ROM), American Orthopaedic Foot and Ankle Score (AOFAS score) and survival rate] of 171 consecutive TAA were analysed and compared before and after surgery. Revision was defined as secondary surgery with prothesis component removal, while reoperation was defined as a non-revisional secondary surgery involving the ankle. RESULTS: At a mean follow-up (FU) period of 7.2 ± 2.7 years (range 2.0 to 14.1 years) there was a significant improvement in ankle ROM (total ROM improved from 25.0° ± 15.0° to 28.7° ± 11.3°, p = 0.015; plantarflexion improved from 18.4° ± 11.7° to 20.6° ± 8.2°, p = 0.044; dorsiflexion improved from 6.6° ± 5.7° to 8.1° ± 4.9°, p = 0.011). AOFAS score increased significantly by 41 ± 15 points after surgery (43.3 ± 11.1 before and 84.3 ± 12.0 after surgery, p < 0.001). Overall survival rate within the FU was 81.3% (95% CI 75.3% to 87.3%) with any secondary surgery, 89.9% (95% CI 84.1% to 93.6%) with revision and 93.6% (95% CI 89.8% to 97.3%) with reoperation as endpoint. CONCLUSION: This study endorses the previously reported appealing intermediate- to long-term outcomes of the Salto Mobile Bearing TAA. There was a significant increase in ROM and AOFAS score as well as decent implant survival at final FU.

Histopathology and Feline Pancreatic Lipase Immunoreactivity in Inflammatory, Hyperplastic and Neoplastic Pancreatic Diseases in Cats.

The most common pancreatic diseases in cats are pancreatitis and exocrine pancreatic insufficiency (EPI). Non-invasive methods, such as serological quantification of feline pancreatic lipase immunoreactivity (fPLI), are often used in the diagnosis of pancreatitis. Previous studies have compared fPLI concentrations with histopathology, considered to be the gold standard for diagnosis of feline pancreatitis. However, fPLI concentrations in cats suffering from pancreatic tumours were rarely described. The aim of the present study was to determine the sensitivity and specificity of an in-house enzyme-linked immunosorbent assay (ELISA) for the quantification of fPLI in serum samples based on histopathological findings in cats diagnosed with various pancreatic diseases. Pancreatic biopsy samples from 80 cats were included. Five groups were defined on the basis of pancreatic histopathology: group 1, normal pancreas; group 2, nodular hyperplasia; group 3, mild pancreatitis; group 4, marked (moderate/severe) pancreatitis; and group 5, pancreatic neoplasia. Serum samples from all cats were tested by fPLI ELISA (<3.6 µg/l normal, 3.6-5.3 µg/l questionable, >5.3 µg/l pancreatitis). In group 1 (n = 19), serum fPLI values were within the reference interval in 74% of cases and in group 2 (n = 9) in 78%. Cats with mild pancreatitis (n = 23), marked pancreatitis (n = 11) and pancreatic neoplasms (n = 18) had significantly increased fPLI concentrations compared with group 1 (P = 0.004/0.001/≤0.0001). Cats with nodular hyperplasia had significantly lower fPLI values than cats with marked pancreatitis (P = 0.048) or tumours (P = 0.002). Serum fPLI concentrations in group 3 were <3.6 µg/l (n = 6), 3.6-5.3 µg/l (n = 4) and >5.3 µg/l (n = 13). Calculated test sensitivity for mild pancreatitis was fPLI >3.5 µg/l: 73.9% and fPLI >5.3 µg/l: 56.5%. In group 4 (n = 11), seven of nine cats (77.8%) with marked purulent pancreatitis had elevated fPLI. In group 4, a sensitivity of 81.8% was detected for fPLI >3.5 µg/l and 63.6% for fPLI >5.3 µg/l. Two cats with marked non-purulent pancreatitis had elevated fPLI, while two cats with marked purulent pancreatitis had normal fPLI values (<3.6 µg/l). In group 5, one cat with pancreatic adenoma and one with pancreatic acinar carcinoma had normal fPLI concentrations. The other cats with pancreatic adenoma (solid, n = 1; cystic, n = 4) or carcinoma (solid, n = 9; cystic, n = 2) had elevated or high fPLI values (4.1 to >40 µg/l, median 21.2 µg/l), probably caused by additional inflammation. The results of the present study confirm the importance of detailed histopathological characterization for the interpretation of clinical signs and fPLI values in feline pancreatitis. Primary pancreatic neoplasms may also lead to elevated fPLI concentrations as there is concurrent pancreatitis in most cases. However, severe pancreatic diseases, such as chronic non-purulent pancreatitis or tumours without inflammation, may result in normal fPLI values.

Pharmacokinetics of posaconazole in koalas (Phascolarctos cinereus) after intravenous and oral administration.

The pharmacokinetic profile of posaconazole in clinically normal koalas (n = 8) was investigated. Single doses of posaconazole were administered intravenously (i.v.; 3 mg/kg; n = 2) or orally (p.o.; 6 mg/kg; n = 6) with serial plasma samples collected over 24 and 36 hr, respectively. Plasma concentrations of posaconazole were quantified by validated high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis of data was performed. Following i.v. administration, estimates of the median (range) of plasma clearance (CL) and steady-state volume of distribution (Vss ) were 0.15 (0.13-0.18) L hr-1  kg-1 and 1.23 (0.93-1.53) L/kg, respectively. The median (range) elimination half-life (t1/2 ) after i.v. and p.o. administration was 7.90 (7.62-8.18) and 12.79 (11.22-16.24) hr, respectively. Oral bioavailability varied from 0.43 to 0.99 (median: 0.66). Following oral administration, maximum plasma concentration (Cmax ; median: 0.72, range: 0.55-0.93 µg/ml) was achieved in 8 (range 6-12) hr. The in vitro plasma protein binding of posaconazole incubated at 37°C was 99.25 ± 0.29%. Consideration of posaconazole pharmacokinetic/pharmacodynamic (PK/PD) targets for some yeasts such as disseminated candidiasis suggests that posaconazole could be an efficacious treatment for cryptococcosis in koalas.

[Interdisciplinary management in geriatric trauma surgery : Results of a survey in Austria]. / Interdisziplinäres Management in der Alterstraumatologie : Ergebnisse einer österreichweiten Umfrage.

BACKGROUND: The treatment of geriatric patients in the field of trauma surgery is increasingly gaining importance. To provide optimized treatment to these mostly multimorbid patients, interdisciplinary treatment concepts between trauma surgeons and geriatricians have been designed and implemented successfully. OBJECTIVES: The aim of this survey was to evaluate the current state of interdisciplinary management in the treatment of geriatric patients on trauma surgery wards throughout Austria. MATERIAL AND METHODS: The directors of 64 Austrian trauma surgery wards were surveyed using an online-questionnaire regarding the current interdisciplinary treatment of geriatric patients. RESULTS: A total of 39 (61 %) questionnaires were analyzed. Of the participating wards, 20 % distinguished between geriatric and non-geriatric patients. There were various criteria to classify the patients. The average percentage of patients older than 70 years was 43 %. Of the participating wards, 26 % had established a periodical cooperation between trauma surgeons and geriatricians and 8 % of the participants stated that there is no interdisciplinary cooperation. The establishment of an interdisciplinary treatment concept in the near future was planned in 28 %. The most commonly mentioned obstacle that prevented trauma surgery wards from establishing an interdisciplinary management model was the lack of personnel resources (59 %) - especially the lack of geriatricians (62 %). CONCLUSION: The survey's results underline the geriatric trauma surgery's great importance especially regarding the high percentage of geriatric patients, as well as the fact that the significance of the interdisciplinary cooperation between trauma surgeons and geriatricians is not yet perceived by the majority of Austrian trauma surgery wards.

The leukemogenicity of Hoxa9 depends on alternative splicing.

Although the transforming potential of Hox genes is known for a long time, it is not precisely understood to which extent splicing is important for the leukemogenicity of this gene family. To test this for Hoxa9, we compared the leukemogenic potential of the wild-type Hoxa9, which undergoes natural splicing, with a full-length Hoxa9 construct, which was engineered to prevent natural splicing (Hoxa9FLim). Inability to undergo splicing significantly reduced in vivo leukemogenicity compared to Hoxa9-wild-typed. Importantly, Hoxa9FLim could compensate for the reduced oncogenicity by collaborating with the natural splice variant Hoxa9T, as co-expression of Hoxa9T and Hoxa9FLim induced acute myeloid leukemia (AML) after a comparable latency time as wild-type Hoxa9. Hoxa9T on its own induced AML after a similar latency as Hoxa9FLim, despite its inability to bind DNA. These data assign splicing a central task in Hox gene mediated leukemogenesis and suggest an important role of homeodomain-less splice variants in hematological neoplasms.

No effect of acute tryptophan depletion on verbal declarative memory in young persons with ADHD.

OBJECTIVE: Animal experiments and studies in adults have shown that the neurotransmitter serotonin (5-HT) plays an important role in learning and memory processes. However, data on this relationship in young persons are scarce, and neurodietary research in this age group is limited compared with the extensive literature on adults. Here, we aimed to explore the effects of a diminished central nervous 5-HT synthesis, which is achieved by acute tryptophan depletion (ATD) Moja-De , on memory function in young males with attention deficit hyperactivity disorder (ADHD). METHOD: Twenty-two male patients with ADHD (ages 9-15 years, mean 10.95 ± 1.17 years) received ATD, thus diminishing central nervous 5-HT synthesis, and a tryptophan-balanced amino acid load (BAL) in a randomized, double-blind, within-subject, crossover design study. Approximately 1.7 h after administration of ATD/BAL, verbal declarative memory was assessed using the 'Auditory Verbal-Learning-Test' (AVLT). RESULTS: There were no significant effects of ATD administration on verbal declarative memory function. CONCLUSION: In this study, changes in 5-HT neurotransmission were not associated with specific aspects of verbal declarative memory in young persons with ADHD. Future studies with healthy control groups that address effects of covarying attentional processes are warranted.

The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice.

The t(10;11)(p13-14;q14-21) translocation, giving rise to the CALM-AF10 fusion gene, is a recurrent chromosomal rearrangement observed in patients with poor prognosis acute myeloid leukemia (AML). Although splicing of the CALM-AF10 fusion transcripts has been described in AML patients, the contribution of different CALM and AF10 domains to in vivo leukemogenesis remains to be defined. We therefore performed detailed structure-function studies of the CALM-AF10 fusion protein. We demonstrate that fusion of the C-terminal 248 amino acids of CALM, which include the clathrin-binding domain, to the octapeptide motif-leucine-zipper (OM-LZ) domain of AF10 generated a fusion protein (termed CALM-AF10 minimal fusion (MF)), with strikingly enhanced transformation capabilities in colony assays, providing an efficient system for the expeditious assessment of CALM-AF10-mediated transformation. Leukemias induced by the CALM-AF10 (MF) mutant recapitulated multiple aspects of full-length CALM-AF10-induced leukemia, including aberrant Hoxa cluster upregulation, a characteristic molecular lesion of CALM-AF10 leukemias. In summary, this study indicates that collaboration of the clathrin-binding and the OM-LZ domains of CALM-AF10 is sufficient to induce AML. These findings further suggest that future approaches to antagonize CALM-AF10-induced transformation should incorporate strategies, which aim at blocking these key domains.

The pharmacokinetics of orally administered ivermectin in African elephants (Loxodonta africana): implications for parasite elimination.

Loxodonta africana are susceptible to a wide variety of parasites that are often treated with the broad spectrum antiparasitic ivermectin (IVM) based on empirical knowledge. The objectives of this study were to 1) measure plasma IVM levels following administration of 0.1 mg/kg IVM p.o., 2) compare plasma IVM levels following administration with regular versus restricted feed rations, 3) measure IVM excretion in feces, and 4) use these findings to generate dosing recommendations for this species. Using a crossover design, six African elephants were divided into two groups. Ivermectin was administered and typical grain rations were either provided or withheld for 2 hr. Blood and fecal samples were collected for 7 days following drug administration. After a 5-wk washout period, groups were switched and the procedure repeated. Plasma and fecal IVM were analyzed using high-performance liquid chromatography. There was no statistically significant difference detected in the pharmacokinetic data between the fed and fasted groups. Peak plasma concentration, area under the curve, and half-life for plasma ranged between 5.41-8.49 ng/ml, 17.1-20.3 ng x day/ml, and 3.12-4.47 day, respectively. High IVM concentrations were detected in feces. The peak concentration values in feces were between 264-311-fold higher than those obtained in plasma. The comparatively large area under the curve and short time to maximum concentration in feces indicate elimination prior to absorption of much of the drug. Plasma IVM concentrations were low when compared to other species. Based on these findings, administration of 0.2-0.4 mg/kg p.o. should be appropriate for eliminating many types of parasites in elephants, and could minimize development of parasite resistance.

Reduced serotonergic functioning changes heart rate in ADHD.

Reduced mean heart rate (HR) was shown to be a biophysiological marker for aggression, which in turn was proven to be related to changed serotonergic neurotransmission. A total of 16 ADHD-diagnosed boys were subjected to rapid tryptophan depletion (RTD) and a placebo in a double-blind within-subject crossover-design. Mean HR was assessed under RTD/placebo. Low impulsive patients behaving aggressively under RTD showed a lowered HR under RTD versus placebo. Diminished 5-HT functioning was associated with lowered HR and aggressive behaviour.

Diminished serotonergic functioning in hostile children with ADHD: tryptophan depletion increases behavioural inhibition.

INTRODUCTION: Serotonergic (5-HT) functioning has been shown to account for a variety of behavioural characteristics, in particular aggressive and impulsive behaviour. This study explored the effects of rapid tryptophan depletion (RTD) and the ensuing reduction of brain 5-HT synthesis on behavioural inhibition in passive avoidance learning assessed in a computerized go/no-go task. METHODS: 22 male patients with an ICD-10 diagnosis of ADHD were administered RTD within an amino acid drink lacking tryptophan, the natural precursor of 5-HT, thus lowering the central nervous 5-HT synthesis rate in a placebo-controlled double-blind within-subject crossover-design. 4 hours after RTD/placebo intake the patients were subjected to a go/no-go task for assessment of behavioural inhibition. RESULTS: Highly hostile aggressive patients showed increased inhibition errors under RTD compared to placebo. Low hostile aggressive patients showed lower rates of inhibition errors and thus better performance under RTD compared to placebo. DISCUSSION: The data suggest that in ADHD levels of trait-aggressive characteristics influence the susceptibility to changed behavioural inhibition after an acute 5-HT dysfunction. The detected influence of 5-HT could also be relevant as regards behavioural inhibition being subject to a developmental change in 5-HT functioning.

Serotonin-induced platelet intracellular Ca2+ response in patients with anorexia nervosa.

INTRODUCTION: Serotonin (5-HT) is involved in the regulation of food intake. In anorexia nervosa there is a disturbance in 5-HT function. The stimulation of 5-HT(2)-receptors in platelets is a useful peripheral model to investigate the cascade of signal transduction and neuronal functioning. METHODS: 25 anorexic female patients between the ages of 11 and 18 years with a mean body mass index (BMI) of 13.9+/-1.3 kg/m(2) participated in this study. The 21 healthy female controls revealed a mean BMI of 20.5+/-2.7 kg/m(2). 5-HT stimulated intracellular Ca(2+) response of the platelets was obtained using the Fura-2 method at the time of admission, during therapy and when the target BMI was reached. RESULTS: We found a significant (p<0.01) decrease in 5-HT-induced Delta[Ca(2+)](i) at admission and a significant (p<0.05) increase of Delta[Ca(2+)](i) during treatment in patients with anorexia nervosa. Anorexic patients with and without comorbid depression had a comparable Ca(2+) release. However, low and high Ca(2+) responders showed a different course of Delta[Ca(2+)](i). The treatment with antidepressants led to a significant increase of Delta[Ca(2+)](i) in those patients with concomitant depression. DISCUSSION: Since the course of Delta[Ca(2+)](i) is not related to BMI or the presence of comorbid depression, we conclude that serotonergic transmission or signaling pathways could be disturbed in patients suffering from anorexia nervosa. One inference of this preliminary study is that administration of antidepressants may be more effective in patients with concomitant depression.

Influence of rapid tryptophan depletion on laboratory-provoked aggression in children with ADHD.

BACKGROUND: The present study investigated the effects of rapid tryptophan depletion (RTD), and the ensuing reduction of central nervous system levels of serotonin (5-HT), upon reactive aggression in patients with attention deficit/hyperactivity disorder (ADHD). Furthermore, it was asked whether the relation between 5-HT function and behavioural aggression in patients is influenced by their age, the intensity of their attention problems or their comorbid symptoms. METHODS: The study employed a double-blind, within-subject crossover design. On day 1, 22 male adolescent patients with ADHD were subjected to RTD and the subsequent reduction of central 5-HT levels. On day 2, they received a tryptophan-balanced amino acid mixture (BAL), which acted as a placebo. On both days, 4.5 h after the intake of the RTD/BAL amino acids, reactive aggressive behaviour was provoked using a competitive reaction time game, which consisted of both high and low provocation conditions. RESULTS: The number of aggressive responses was significantly higher after low provocation during acute tryptophan depletion, in comparison to the placebo. Furthermore, this study provides evidence that neither age nor the intensity of attention symptoms in ADHD patients had an impact on the relation between 5-HT and reactive aggression. CONCLUSION: This study indicates that in children with ADHD, there is an inverse relationship between 5-HT and aggression.

DNA vaccines: safety aspect assessment and regulation.

For licensing purposes, besides the immunogenic aspects, deoxyribonucleic acid (DNA) vaccines present safety considerations that must be critically assessed during preclinical or/and clinical safety studies. The major concerns with regard to safety are integration of the plasmid DNA into the host genome, adverse immunopathological effects, the formation of anti-DNA antibodies resulting in auto-immune disease and the use of novel molecular adjuvants. Moreover, for veterinary vaccines intended to be used in husbandry animals, food safety aspects will become an important issue. All new vaccine candidates should therefore be thoroughly tested in target animals, keeping in mind that for food producing animals, the products will be consumed. Finally, a further safety aspect of interest concerns the possible spread of genetic material to the environment, by the potential transformation of the environmental microflora with only a few copies of complete or fragmented plasmid. These are issues that need to be considered in the final scientific decisions underpinning the registration of vaccines. Thus, to establish criteria for guidance and regulations for industry and licensing authorities, a project has been initiated to assess such risks of plasmid DNA vaccinations. Major emphasis will be placed on aspects such as the biodistribution of plasmid in vaccinated animals. This paper is intended as a contribution to the debate on the use of biotechnology in the future and should facilitate further discussions on the various safety aspects of DNA-based immunisations.

Platelet 5-HT uptake in boys with conduct disorder.

Dysregulation of serotonergic function has been found to be associated with aggression in animals, human adults and adolescents. However, studies with children have shown conflicting results. The objective of this study was to investigate whether the kinetic characteristics (Vmax and Km) of 5-HT uptake in platelets are different in children with the diagnosis of conduct disorder according to ICD-10 and healthy age-matched controls. In addition to the standardized assessment of general psychopathology, methods assessing narrowband aggressive symptoms (Child Behavior Checklist) and emotional reactivity to an experimentally induced provocation (Taylor's competitive reaction time task) were used in both groups. We found a trend for a lower mean Vmax of platelet 5-HT uptake in 14 conduct-disordered boys compared with healthy controls (n=15). If, however, 2 patients with a low degree of aggression and emotional reactivity were excluded, the difference became significant (mean=4.27, SD=3.49 in patients and mean=8.45, SD=4.63 in controls). A significant negative correlation was found between parent-rated aggression scores and Vmax (r=-0.41, p < 0.05, n=29). These data suggest that dysfunction of 5-HT transport mechanisms might be associated with specific behavioral symptoms in conduct-disordered children.

Myocardial necrosis in a captive binturong (Arctictis binturong).

An adult male binturong, Arctictis binturong, which had been anorexic and lethargic for seven days became acutely dyspnoeic and died under anaesthesia. A postmortem examination revealed left ventricular hypertrophy with a thrombus occluding the left ventricular chamber. Histological findings included moderate to severe multifocal, vasculocentric myocardial degeneration and necrosis with fibrosis replacing myocardiocytes. Escherichia coli and Proteus mirabilis were grown on cultures. The animal's serum vitamin E and selenium levels were considered adequate. The aetiology of the chronic myocardial changes could not be determined.

Synthetic peptides which inhibit the interaction between C1q and immunoglobulin and prolong xenograft survival.

BACKGROUND: Acute vascular xenograft rejection (AVXR), also termed delayed xenograft rejection (DXR), occurs when hyperacute rejection (HAR) is prevented by strategies directed at xenoreactive natural antibodies and/or complement activation. We have hypothesized that AVXR/DXR is initiated in part by early components of the complement cascade, notably C1q. We have developed synthetic peptides (termed CBP2 and WY) that interfere with the interaction between C1q and antibody. METHODS: CBP2 and the WY-conjugates were used as inhibitors of immunoglobulin aggregate binding to solid phase C1q. Inhibition of complement activation by the peptides of the classical system was determined using lysis assays with sensitized sheep red blood cells or porcine aortic endothelial cells as targets and of the alternate complement pathway using guinea pig red blood cells as targets. Two transplant models were used to study the effects of administering peptides to recipients: rat heart transplant to presensitized mouse, and guinea heart transplant to PVG C6-deficient rats. RESULTS: CBP2 and WY-conjugates inhibited immunoglobulin aggregate binding to C1q. The peptides also inhibited human complement-mediated lysis of sensitized sheep red blood cells and porcine aortic endothelial cells in a dose-dependent manner and the WY-conjugates prevented activation of the alternate complement pathway as shown by inhibition of guinea pig red blood cells lysis with human serum. In addition, the use of the peptides and conjugates resulted in significant prolongation of xenograft survival. CONCLUSIONS: The CBP2 and WY peptides exhibit the functional activity of inhibition of complement activation. These peptides also prolong xenograft survival and thus provide reagents for the study of the importance of C1q and other complement components in transplant rejection mechanisms.